Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions
Abstract Macromolecular crowding effects on globular proteins, which usually adopt a single stable fold, have been widely studied. However, little is known about crowding effects on fold-switching proteins, which reversibly switch between distinct folds. Here we study the mutationally driven switch...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-023-00995-2 |
| _version_ | 1797577609250340864 |
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| author | Saman Bazmi Bahman Seifi Stefan Wallin |
| author_facet | Saman Bazmi Bahman Seifi Stefan Wallin |
| author_sort | Saman Bazmi |
| collection | DOAJ |
| description | Abstract Macromolecular crowding effects on globular proteins, which usually adopt a single stable fold, have been widely studied. However, little is known about crowding effects on fold-switching proteins, which reversibly switch between distinct folds. Here we study the mutationally driven switch between the folds of GA and GB, the two 56-amino acid binding domains of protein G, using a structure-based dual-basin model. We show that, in the absence of crowders, the fold populations P A and P B can be controlled by the strengths of contacts in the two folds, κ A and κ B. A population balance, P A ≈ P B, is obtained for κ B/κ A = 0.92. The resulting model protein is subject to crowding at different packing fractions, ϕ c. We find that crowding increases the GB population and reduces the GA population, reaching P B/P A ≈ 4 at ϕ c = 0.44. We analyze the ϕ c-dependence of the crowding-induced GA-to-GB switch using scaled particle theory, which provides a qualitative, but not quantitative, fit of our data, suggesting effects beyond a spherical description of the folds. We show that the terminal regions of the protein chain, which are intrinsically disordered only in GA, play a dominant role in the response of the fold switch to crowding effects. |
| first_indexed | 2024-03-10T22:10:28Z |
| format | Article |
| id | doaj.art-8d7297f8c60746fb9e39f4578e866060 |
| institution | Directory Open Access Journal |
| issn | 2399-3669 |
| language | English |
| last_indexed | 2024-03-10T22:10:28Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj.art-8d7297f8c60746fb9e39f4578e8660602023-11-19T12:37:30ZengNature PortfolioCommunications Chemistry2399-36692023-09-01611910.1038/s42004-023-00995-2Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regionsSaman Bazmi0Bahman Seifi1Stefan Wallin2Department of Physics and Physical Oceanography, Memorial University of NewfoundlandDepartment of Physics and Physical Oceanography, Memorial University of NewfoundlandDepartment of Physics and Physical Oceanography, Memorial University of NewfoundlandAbstract Macromolecular crowding effects on globular proteins, which usually adopt a single stable fold, have been widely studied. However, little is known about crowding effects on fold-switching proteins, which reversibly switch between distinct folds. Here we study the mutationally driven switch between the folds of GA and GB, the two 56-amino acid binding domains of protein G, using a structure-based dual-basin model. We show that, in the absence of crowders, the fold populations P A and P B can be controlled by the strengths of contacts in the two folds, κ A and κ B. A population balance, P A ≈ P B, is obtained for κ B/κ A = 0.92. The resulting model protein is subject to crowding at different packing fractions, ϕ c. We find that crowding increases the GB population and reduces the GA population, reaching P B/P A ≈ 4 at ϕ c = 0.44. We analyze the ϕ c-dependence of the crowding-induced GA-to-GB switch using scaled particle theory, which provides a qualitative, but not quantitative, fit of our data, suggesting effects beyond a spherical description of the folds. We show that the terminal regions of the protein chain, which are intrinsically disordered only in GA, play a dominant role in the response of the fold switch to crowding effects.https://doi.org/10.1038/s42004-023-00995-2 |
| spellingShingle | Saman Bazmi Bahman Seifi Stefan Wallin Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions Communications Chemistry |
| title | Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions |
| title_full | Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions |
| title_fullStr | Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions |
| title_full_unstemmed | Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions |
| title_short | Simulations of a protein fold switch reveal crowding-induced population shifts driven by disordered regions |
| title_sort | simulations of a protein fold switch reveal crowding induced population shifts driven by disordered regions |
| url | https://doi.org/10.1038/s42004-023-00995-2 |
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